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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1370-1378.
Prepublished online as a Blood First Edition Paper on April 13, 2007; DOI 10.1182/blood-2007-03-081497.
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Submitted March 22, 2007
Accepted April 11, 2007
Reversal of autoimmune disease in lupus-prone NZB/NZW mice by nonmyeloablative transplantation of purified allogeneic hematopoietic stem cells
Stephanie Smith-Berdan, Daphne Gille, Irving L. Weissman, and Julie L. Christensen*
Cellerant Therapeutics, San Carlos, CA, United States
Stanford University School of Medicine, Stanford, CA, United States
* Corresponding author; email: jchristensen{at}cellerant.com.
Patients with severe Systemic Lupus Erythematosus (SLE) refractory to conventional treatment are candidates for autologous hematopoietic (stem) cell (HSC) transplantation if the intent is to re-set the immunological clock. SLE patients might be candidates for allotransplantation with SLE resistant MHC haplotype matched HSC if partial or complete replacement of an autoimmune-prone system is the intent. Using lupus prone NZB x NZW (NZBW) mice, we investigated the use of highly enriched, haplo-mismatched allogeneic HSC to prevent development or to treat established autoimmune pathology. Young, NZBW mice transplanted with purified allogeneic HSC had improved overall survival, decreased appearance of proteinuria, of circulating immune complexes (CIC), and of auto-antibodies to nuclear antigens than untreated mice or mice given NZBW HSC. NZBW mice with established lupus-like disease that received nonmyeloablative conditioning and transplantation with MHC haplo-mismatched allogeneic HSC also had greatly increased overall survival. Transplanted mice exhibited stabilization or reversal of their lupus symptoms; stabilization of or decreased proteinuria, and the frequency of mice with elevated CIC or auto-antibodies were lower in the transplanted mice than various control mice. Induction of durable mixed chimerism by transplantation of purified allogeneic HSC after nonmyeloablative conditioning has the potential to reverse symptoms of established NZBW lupus.
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